Diquaternary salts of papaverino esters



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3 031 tion. The residue was washed three times with hot ben- DIQUATERNARY yg 0F PAPAVERINO 'zene by decantation, dried and dissolved in methanol.

ESTERS The solution thus obtained was added drop by drop to Ed i P i l Taylor, Henry a ld J k C lli mechanically stirred ether. The precipitate was filtered and Jan Mieczyslaw Zygmunt Gladych, all of London, 5 oh and was further purified by twice reprecipitating in g g g i' g 'inf i & HfiHbuiYS Limited, Lona similar manner. The product was a cream-coloured Hg an a a n t microc stalline owder. No Drawing. Filed July 1, 1959, der. No. 824,132 012N231 requires: N 2 Br 15.3% tjlauns priority, application Great Britfin July 3, 1958 g N 2 77 Br 15 87 5 Claims. or. zen-ass Y 10 EXAMPLE 3 This invention relates to new heterocyclic compounds. The compounds of the present invention are diquater- Prepa'atwn of the 'dlbwmlfie of b's-[p'(N'methyl'tetm hydro-papavermo) ethyl] oxalate nary salts of his -[w-(tetrahydro-papaverino)alkyl] esters of aliphatic dicarboxylic acids of the general formula: 1.8 gm. of laudanosine, 0.5 g. of S-bromoethyl oxalate where R is a lower alkyl group containing not more than and ml. of dry benzene were refluxed together for 6 carbon atoms; X is an anion; m is 2 or 3 and n is 0, 1, 2,3 or 4. cooling, the benzene was removed by decantation and The preferred compounds are the dibromide and di- 39 the residue was washed three times with hot benzene iodide of 'bis-[ y-(lfJ-methyhtetrahydro-papaverino)proand dried. The solid residue was purified by dissolving pyl] oxalate. it in anhydrous ethanol and adding the solution thus The present invention also includes a process for preformed drop by drop to mechanically stirred ether. The paring the compounds of the present invention, which precipitate was filtered off and twice reprecipitated in a comprises refluxing an excess of an N-alkyl tetrahydro 5 similar manner. The product was a cream-coloured pap-averine with an w-bromalkyl dicarboxylate in an powder. inert solvent for a prolonged period, e.g., several days. C H O N Br requires: N, 2.75%; Br, 15.7%. The inert solvent may, for example, be an aromatic hy- Found: N, 3.0%; Br, 16.0%. drocarbon such as benzene.

The present invention further includes a process for 40 EXAMPLE 4 Preparing the PmPounds of the Presemf invention which Preparation of the dibromia'e of bis-[fi-(N-methyl-tetracomprises reacting an w-bromoalkyl dicarboxylate with hydm papaverino)ethyllglummte 3.1 gm. of laudanosine, 1.0 g. of B-bromoethyl glutetrahydro papaverine, and treating the product obtained with at least 2 molecular proportions of an alkyl halide tarate and 40 ml. of dry benzene were refluxed together or sulphate.

The compounds of this invention are useful as muscle for 425 hours. After removal of the benzene by decantarelaxants. tion the gummy residue was washed three times with hot The following examples illustrate the invention: benzene and dried. The residue was purified by dissolving in anhydrous ethanol and adding the solution thus EXAMPLE 1 formed drop by drop to mechanically stirred ether. The

Prepa at on Of the dibi'vmide f -[fl-( y precipitate was filtered oii and reprecipitated twice in a hydro-papaverino)ethyl]malonate similar manner. The product was a cream-coloured 1.7 gm. of laudanosine, 0.5 g. of ,(3-brornoethyl malopowder' nate and 20 ml. of dry benzene were refluxed together CEIHGBOIZNZBIZ reqmres: 25%; 151%- for 300 hours. The product which separated hardened Found: N2'65%3B1314-5%' on cooling and was removed by filtration, washed with EXAMPLE 5 benzene and dried. The solid residue was purified by dissolving in anhydrous ethanol and adding the solution Preparation 0 the dibromide of bis-[fl-(N-methyl-tetrathus formed drop by drop to mechanically stirred ether. hydro-papaverino)ethyl]aa'ipate The precipitate was filtered oif and reprecipitated in a similar manner. The product was a cream-coloured microcrystalline powder.

1.4 gm. of laudanosine, 0.5 g. of fl-bromoethyl adipate and 20 ml. of dry benzene were refluxed together for p 950 hours. The product was a thick gum from which ggfifg figgg i' 155% the benzene was removed by decantation and the residue washed three times with hot benzene and dried. The EXAMPLE 1 residue was purified by dissolving in anhydrous ethanol Preparation of the dibromide of bis-[fi-(N-methyl-tetraand adding the solution thus formed drop by drop to hydro-papaverino)ethyl1succinate mechanically stirred ether. The precipitate was filtered 32 gm. of laudanosine, 1.0 g. of fibromoethyl Succi oif and reprecipitated twice in a similar manner. The nate and 25 ml. of dry benzene were refluxed together Product was a cream-wloured P for 134 hours. The products of the reaction was a thick 52 7o 12 2 '2 Tequiresi gum from which the benzene was removed by decanta- Found: N, 2.85 %;Br, 14.6%.

416 hours. The product which separated hardened on 3 EXAMPLE 6 2.9 gm. of N-ethyl-tetrahydropapaverine, 1.0 g. of fl-bromoethyl adipate and 40 ml. of dry benzene were refluxed together for 1400 hours. After removal of the benzene by decantation the gummy residue was washed three times with hot benzene and dried. The residue was purified by dissolving in anhydrous ethanol and adding the solution thus formed drop by drop to mechanically stirred ether. The precipitate was filtered oit and reprecipitated twice in a similar manner. The product was a cream-coloured powder.

C54H74O12N2BI'2 requires: N, 2.5 Br, 14.45%.

Found: N, 2.7%; Br, 15.0%.

EXAMPLE 7 Preparation of the dibromide of his-[fl-(N-ethyl-tetrahydro-papaverino) ethyl] malonate 1.8 gm. of N-ethyl-tetrahydro-papaverine, 0.5 g. of B- bromo-ethyl malonate and 20 ml. of dry benzene were refluxed together for 1500 hours. The benzene was removed by decantation from the thick gummy residue which was then washed three times with hot benzene and dried. The residue was purified by dissolving in anhydrous ethanol and adding the solution thus formed drop by drop to mechanically stirred ether. The precipitate was filtered off and twice reprecipitated in a similar manner. The product was a creamed-coloured powder.

C H O N Br requires: N, 2.6%; Br, 15.1%. Found: N, 2.7%; Br, 15.8%.

EXAMPLE 8 Preparation of tlte dibromide of bis-['y-(N-methyl-tetrahydro-papaverino) propyl] oxalate EXAMPLE 9 Preparation of the dibromide of bis-['y-(N-methyl-tetrahydro-papaverino) propyl] malonate N, 2.7%; Br, 15.3%.

1.8 gm. of laudanosine, 0.58 g. of v-bromopropyl malonate and 30 ml. of dry benzene were refluxed together for 520 hours. After removal of the benzene by decantation the gummy residue was washed three times with hot benzene and dried. The solid was purified by dissolving in anhydrous ethanol and adding the solution thus formed drop by drop to mechanically stirred ether. The precipitate was filtered olf and reprecipitated twice in a similar manner. The product was a cream-coloured powder.

C H O N Br requires: Found: N, 2.6%; Br, 15.0%.

EXAMPLE Preparation of the diperchlorate of bis-[,3-(N-methyltetrahydro-papaverino) ethyl] malonate 0.18 gm. of the dibromide of bis-[B-(N-methyltetra- N, 2.6%; Er, 15.1%.

hydro papaverino)ethyllmalonate, dissolved in 10 ml. of water was filtered and added dropwise to a solution of 0.1 g. of sodium perchlorate in 5 ml. of water. The precipitate was removed by filtration, washed with water, dried and recrystallised from dimethyl formamide and ether. The product was a bull-coloured compound.

C H O N Cl requires: N, 2.6%; Cl, 6.6%. Found: N, 2.6%; Cl, 6.55%.

EXAMPLE 11 Preparation of the dinitrate of bis-[p-(N-methyl-tetrahydro-papaverino) ethyl] oxalate 0.07 gm. of the dibromide of bis-[B-(N-methyltetrahydro-papaverino)ethyl]oxalate, dissolved in 2 ml. of anhydrous ethanol was added dropwise to a solution of 0.012 g. of silver nitrate in 16 m1. of anhydrous ethanol. The reaction mixture was refluxed for 30 minutes, allowed to cool and filtered. An excess of anhydrous ether was added to the filtrate and the precipitate removed by filtration. The product was purified by redissolving in anhydrous ethanol and adding the solution thus formed drop by drop to mechanically stirred ether. The precipitate was filtered OE and reprecipitated once in a similar manner. The product was a buff-coloured powder.

C48H62018N4 requires: N, 5.76%. Found: N, 5.75%.

EXAMPLE 12 Preparation of the diperchlorate of bis-['y-(N-methyltetrahydro-papaverino) propyl] oxalate 1.0 gm. of the dibromide of bis-[q-(N-methyltetrahydro-papaverino)propylloxalate, dissolved in 15 ml. of water was added dropwise to a solution of 0.24 gm. of sodium perchlorate in 15 ml. of water. The precipitate was removed by filtration, washed with water, dried, dissolved in anhydrous acetone, and reprecipitated with anhydrous ethanol. After a further purification in a similar manner the product was a yellow powder.

C5oH 020N2Cl2 requires: N, Cl, 6.5%. Found: N, 2.6%; Cl, 6.1%.

EXAMPLE 13 Preparation of the di-iodide of bis-['y-(N-methyl-tetrahydro-papaverino propyl] Oxalate 4.7 gm. of tetrahydro-papaverine hydriodide was added to an excess of 2 N sodium hydroxide solution, and the liberated base completely extracted with benzene. The combined benzene extracts were washed with water and dried over anhydrous magnesium sulphate. The extract was separated by filtration and the solvent removed by distillation. The remaining light brown oil was dissolved in 50 ml. of anhydrous acetone. 1.52 gm. of anhydrous potassium carbonate and 1.66 gm. of bis(' -bromopropyl)- oxalate, dissolved in 50 ml. of anhydrous acetone, were added to the acetone solution of tetrahydro-papaverine and refluxed together for 104 hours. The solution was cooled and separated by filtration. The solvent was removed by distillation under reduced pressure. Bis-[' (tetrahydro-papaverino)propyl]oxalate was obtained as a light brown oil (4.5 gm).

1 ml. of methyl iodide was added to a solution of 2.25 gm. of bis[' -(N-tetrahydro-papaverino)propylloxalate in 10 ml. of anhydrous acetone. The solution was allowed to stand for 1.5 hours and then refluxed for 1.5 hours. The oil which separated crystallised after the addition of anhydrous ether. The product was a pale yellow powder.

C H O N I requires: N, 2.45%; I, 22.2%. Found: N, 2.5%; I, 22.7%.

The dibromide of bis-[ y-(N-methyl-tetrahydro-papaverino)propyl]oxalate when administered intravenously to mice in effective doses produced paralysis which was not preceded nor followed by excitation. The paralysing activity of the drug was determined in mice and the results of these experiments are summarised in Table I:

The compounds of the present invention were examined by intravenous administration to cats, maintained by artificial ventilation and prepared for recording the isometric twitch of the tibialis anterior muscle in response to stimulation of its motor nerve. The duration of activity of the neuro muscular blocking action was compared wtih that of suxamethonium chloride. The results of these experiments are given in Table ll:

OH3O

CHaO

TABLE II Compound in which R, m, Duration n and X of the general forof action mula have the values- No. of as comcats pared with sux- R m n X amethnium (=1) CH 2 2 Br 3 5. 4 CH3 2 1 Br 8 2. 6 CH3 3 1 Br 3 9.0 CH3 3 0 Br 8 0.

OB O

-In each case Neostigmine was found to be an effective antagonist. The cumulative action of suxarnethoniurn chloride and the dibromide of his -(N-methyl-tetrahydropapaverino)propyl] oxalate were compared in three cats in which series of successive equal doses of one sub- TABLE III dibromide of bis-I-y-(N- Suxametlfinlum, 50 methyl-tetrahydropa- From these results it will be seen that the compounds of the present invention have no significant cumulative effect.

What we claim is: 1. Salts of the formula:

R R OCH! N (0H=)m0;0o-(onon-ooo-(oflom n OCH CH3 H3 where R is a lower alkyl group of less than 7 carbon atoms, X is a non-toxic inorganic ion, m1 is one of the integers 2 and 3 and n is selected from the group consisting of zero, 1, 2, 3 and 4.

2. The dibromide of bis-[y-(N-methyhtetrahydropapaverino) propyl] oxalate.

3. The di-iodide of bis-['y-(N-methyl-tetrahydro-papa- 40 verino)propyl] oxalate.

' 4. A process for preparing salts of the formula:

R R OCH3 N CH z)m-0.00 o112)no0.0(oHg)m N x X (11 OH:

OCH:

0 CHa integers 2 and 3 and n is selected from the group 0011- sisting of zero, 1, 2, 3 and 4, which comprises refluxing an N-alkyl tetrahydropapaver-ine with an W-bromalkyl dicarboxylate in an inert organic solvent for a period of stance were given at equal intervals of time. The re 2 5 thanfloo E- and isolating and Purifying the V n rest mg reac 1011 pro uct.

sults of this experiment are given in T aole ill. 5. A process for P p g Salts of the formula:

r 7 where R is a lower alkyl group of less than 7 carbon atoms, X is a non-toxic inorganic ion, m is one of the integers 2 and 3 and n is selected from the group consisting of zero, 1, 2, 3 and 4, which comprises reacting an w-bromalkyl dicarboxylate with tetrahydropapaverine in an inert, anhydrous organic solvent under reflux for at least about 100 hours, isolating the resulting reaction product, dissolving it in the same solvent, adding to the solution a lower alkyl compound selected from the group consisting of lower alkyl halides and lower alkyl sulfate 5 and isolating the product thus formed.

No references cited. 

1. SALTS OF THE FORMULA: 